Benjamin, Emelia J.

Rationale: GWAS (Genome-Wide Association Studies) have identified hundreds of genetic loci associated with atrial fibrillation (AF). However, these loci explain only a small proportion of AF heritability. Objective: To develop an approach to identify additional AF-related genes by integrating multiple omics data. Methods and Results: Three types of omics data were integrated: (1) summary statistics from the AFGen 2017 GWAS; (2) a whole blood EWAS (Epigenome-Wide Association Study) of AF; and (3) a whole blood TWAS (Transcriptome-Wide Association Study) of AF. The variant-level GWAS results were collapsed into gene-level associations using fast set-based association analysis. The CpG-level EWAS results were also collapsed into gene-level associations by an adapted SNP-set Kernel Association Test approach. Both GWAS and EWAS gene-based associations were then meta-analyzed with TWAS using a fixed-effects model weighted by the sample size of each data set. A tissue-specific network was subsequently constructed using the NetWAS (Network-Wide Association Study). The identified genes were then compared with the AFGen 2018 GWAS that contained more than triple the number of AF cases compared with AFGen 2017 GWAS. We observed that the multiomics approach identified many more relevant AF-related genes than using AFGen 2018 GWAS alone (1931 versus 206 genes). Many of these genes are involved in the development and regulation of heart- and muscle-related biological processes. Moreover, the gene set identified by multiomics approach explained much more AF variance than those identified by GWAS alone (10.4% versus 3.5%). Conclusions: We developed a strategy to integrate multiple omics data to identify AF-related genes. Our integrative approach may be useful to improve the power of traditional GWAS, which might be particularly useful for rare traits and diseases with limited sample size.

Catheter ablation has brought major advances in the management of patients with atrial fibrillation (AF). As evidenced by multiple randomized trials, AF catheter ablation can reduce the risk of recurrent AF and improve quality of life. In some studies, AF ablation significantly reduced cardiovascular hospitalizations. Despite the existing data on AF catheter ablation, numerous knowledge gaps remain concerning this intervention. This report is based on a recent virtual workshop convened by the National Heart, Lung, and Blood Institute to identify key research opportunities in AF ablation. We outline knowledge gaps related to emerging technologies, the relationship between cardiac structure and function and the success of AF ablation in patient subgroups in whom clinical benefit from ablation varies, and potential platforms to advance clinical research in this area. This report also considers the potential value and challenges of a sham ablation randomized trial. Prioritized research opportunities are identified and highlighted to empower relevant stakeholders to collaborate in designing and conducting effective, cost-efficient, and transformative research to optimize the use and outcomes of AF ablation.

Background Tools for the prediction of atrial fibrillation ( AF ) may identify high‐risk individuals more likely to benefit from preventive interventions and serve as a benchmark to test novel putative risk factors. Methods and Results Individual‐level data from 3 large cohorts in the U nited S tates (Atherosclerosis Risk in Communities [ ARIC ] study, the Cardiovascular Health Study [ CHS ], and the Framingham Heart Study [ FHS ]), including 18 556 men and women aged 46 to 94 years (19% A frican A mericans, 81% whites) were pooled to derive predictive models for AF using clinical variables. Validation of the derived models was performed in 7672 participants from the Age, Gene and Environment—Reykjavik study ( AGES ) and the Rotterdam Study ( RS ). The analysis included 1186 incident AF cases in the derivation cohorts and 585 in the validation cohorts. A simple 5‐year predictive model including the variables age, race, height, weight, systolic and diastolic blood pressure, current smoking, use of antihypertensive medication, diabetes, and history of myocardial infarction and heart failure had good discrimination (C‐statistic, 0.765; 95% CI , 0.748 to 0.781). Addition of variables from the electrocardiogram did not improve the overall model discrimination (C‐statistic, 0.767; 95% CI , 0.750 to 0.783; categorical net reclassification improvement, −0.0032; 95% CI , −0.0178 to 0.0113). In the validation cohorts, discrimination was acceptable ( AGES C‐statistic, 0.664; 95% CI , 0.632 to 0.697 and RS C‐statistic, 0.705; 95% CI , 0.664 to 0.747) and calibration was adequate. Conclusion A risk model including variables readily available in primary care settings adequately predicted AF in diverse populations from the U nited S tates and E urope.

Background— Data regarding the familial aggregation of left ventricular (LV) geometry and its relations to parental heart failure (HF) are limited. Methods and Results— We evaluated concordance of LV geometry within 1093 nuclear families in 5758 participants of the original (parents) (n=2351) and offspring (n=3407) cohorts of the Framingham Heart Study undergoing routine echocardiography in mid- to late adulthood. LV geometry was categorized based on cohort- and sex-specific 80th percentile cutoffs of LV mass and relative wall thickness (RWT) into normal (both <80th percentile), concentric remodeling (LV mass <80th percentile; RWT >80th percentile), concentric hypertrophy (both >80th percentile), and eccentric hypertrophy (LV mass >80th percentile; RWT <80th percentile). Within nuclear families, LV geometry was concordant among related pairs (parent-child, sibling-sibling) ( P =0.0015) but not among unrelated spousal pairs ( P =0.60), a finding that remained unchanged after adjusting for clinical covariates known to influence LV remodeling (age, systolic blood pressure, body mass index), excluding individuals with prevalent HF and myocardial infarction, and varying the thresholds for defining LV geometry. The prevalence of abnormal LV geometry was higher in family members of affected individuals, with recurrence risks of 1.4 for concentric remodeling (95% CI, 1.2 to 1.7) and eccentric hypertrophy (95% CI, 1.1 to 1.8) and 3.9 (95% CI, 3.2 to 4.6) for concentric hypertrophy. In a subset of 1497 offspring, we observed an association between parental HF (n=458) and eccentric hypertrophy in offspring ( P <0.0001). Conclusions— Our investigation of a 2-generational community-based sample demonstrates familial aggregation of LV geometry, with the greatest recurrence risk for concentric LV geometry, and establishes an association between eccentric LV geometry and parental HF.

Background— Aortic root remodeling in adulthood is known to be associated with cardiovascular outcomes. However, there is a lack of longitudinal data defining the clinical correlates of aortic root remodeling over the adult life course. Methods and Results— We used serial routine echocardiograms in participants of the Framingham Heart Study to track aortic root diameter over 16 years in mid to late adulthood and to determine its short-term (4 years; n=6099 observations in 3506 individuals) and long-term (16 years; n=14 628 observations in 4542 individuals) clinical correlates by multilevel modeling. Age, sex, body size, and blood pressure were principal correlates of aortic remodeling in both short- and long-term analyses (all P ≤0.01). Aortic root diameter increased with age in both men and women but was larger in men at any given age. Each 10-year increase in age was associated with a larger aortic root (by 0.89 mm in men and 0.68 mm in women) after adjustment for body size and blood pressure. A 5-kg/m 2 increase in body mass index was associated with a larger aortic root (by 0.78 mm in men and 0.51 mm in women) after adjustment for age and blood pressure. Each 10-mm Hg increase in pulse pressure was related to a smaller aortic root (by 0.19 mm in men and 0.08 mm in women) after adjustment for age and body size. Conclusions— These longitudinal community-based data show that aortic root remodeling occurs over mid to late adulthood and is principally associated with age, sex, body size, and blood pressure. The underlying basis for these differences and implications for the development of cardiovascular events deserve further study.

Background— Few data have evaluated physician adherence to cardiovascular disease (CVD) prevention guidelines according to physician specialty or patient characteristics, particularly gender. Methods and Results— An online study of 500 randomly selected physicians (300 primary care physicians, 100 obstetricians/gynecologists, and 100 cardiologists) used a standardized questionnaire to assess awareness of, adoption of, and barriers to national CVD prevention guidelines by specialty. An experimental case study design tested physician accuracy and determinants of CVD risk level assignment and application of guidelines among high-, intermediate-, or low-risk patients. Intermediate-risk women, as assessed by the Framingham risk score, were significantly more likely to be assigned to a lower-risk category by primary care physicians than men with identical risk profiles ( P <0.0001), and trends were similar for obstetricians/gynecologists and cardiologists. Assignment of risk level significantly predicted recommendations for lifestyle and preventive pharmacotherapy. After adjustment for risk assignment, the impact of patient gender on preventive care was not significant except for less aspirin ( P <0.01) and more weight management recommended ( P <0.04) for intermediate-risk women. Physicians did not rate themselves as very effective in their ability to help patients prevent CVD. Fewer than 1 in 5 physicians knew that more women than men die each year from CVD. Conclusions— Perception of risk was the primary factor associated with CVD preventive recommendations. Gender disparities in recommendations for preventive therapy were explained largely by the lower perceived risk despite similar calculated risk for women versus men. Educational interventions for physicians are needed to improve the quality of CVD preventive care and lower morbidity and mortality from CVD for men and women.